We have identified three cross reactive idiotypes on anti-double stranded DNA antibodies in systemic lupus erythematosus in man. The 3I kappa light chain idiotype is encoded by the Vk1 gene family; the F4 heavy chain idiotype by the VH3 or VH4 gene family and the 8.12 lambda light chain idiotype by the V2 gene family. Having identified the V gene families associated with the cross reactive idiotypes, we now propose to determine if particular members of these V region families encode anti-DNA antibodies and if there are polymorphisms of these V region genes that predispose to SLE. We will study multiple antibodies produced by clonally related B cell lines, B cell genealogies, to identify structural determinants of DNA binding and assess the role of antigen, and DNA in particular in the anti- DNA response. We will determine the relationship of idiotypic anti-DNA antibodies to anti-pneumococcal polysaccharide antibodies bearing the 3I or 8.12 cross-reactive idiotype. Finally, we will initiate studies aimed at defining the structural correlates of pathogenicity of anti-DNA antibodies and at identifying the T cells that participate in the anti-DNA response in SLE.